Feline leukemia virus subgroup C receptor 1 (
Flvcr1) encodes two heme exporters: FLVCR1a, which localizes to the plasma membrane, and FLVCR1b, which localizes to mitochondria. Here, we investigated the role of the two
Flvcr1 isoforms during erythropoiesis. We showed that, in mice and zebrafish,
Flvcr1a is required for the expansion of committed erythroid progenitors but cannot drive their terminal differentiation, while
Flvcr1b contributes to the expansion phase and is required for differentiation.
FLVCR1a-down-regulated K562 cells have defective proliferation, enhanced differentiation, and heme loading in the cytosol, while
FLVCR1a/1b-deficient K562 cells show impairment in both proliferation and differentiation, and accumulate heme in mitochondria. These data support a model in which the coordinated expression of
Flvcr1a and
Flvcr1b contributes to control the size of the cytosolic heme pool required to sustain metabolic activity during the expansion of erythroid progenitors and to allow hemoglobinization during their terminal maturation. Consistently, reduction or increase of the cytosolic heme rescued the erythroid defects in zebrafish deficient in
Flvcr1a or
Flvcr1b, respectively. Thus, heme export represents a tightly regulated process that controls erythropoiesis.
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